tbuckley/cabot-search huggingface dataset:
Efficacy, Safety, and Health-Related Quality of Life With Camrelizumab Plus Pemetrexed and Carboplatin as First-Line Treatment for Advanced Nonsquamous NSCLC With Brain Metastases (CAP-BRAIN): A Multicenter, Open-Label, Single-Arm, Phase 2 Study
Authors: Xue Hou, Chengzhi Zhou, Guowu Wu, Wen Lin, Zhanhong Xie, Haibo Zhang, Jiqun Yi, Zheng Peng, Lifeng Yin, Chi Ma, Likun Chen
Journal: Journal of Thoracic Oncology (2023)

Systemic treatment options for NSCLC with brain metastases (BMs) are scarce. We evaluated the activity and safety of camrelizumab plus chemotherapy as first-line therapy in patients with advanced nonsquamous NSCLC with BMs. This was a multicenter, single-arm, phase 2 trial (NCT04211090) conducted at seven hospitals in China. Eligible patients had treatment-naive metastatic nonsquamous NSCLC and BMs that were asymptomatic or symptoms controlled with dehydration therapy and no previous systemic treatment or local therapy for the target brain lesion. Patients received camrelizumab (200 mg) plus pemetrexed (500 mg/m2) and carboplatin (area under the curve 5) intravenously on day 1 of each 21-day cycle for four cycles, followed by maintenance with camrelizumab (200 mg) and pemetrexed (500 mg/m2) every 21 days until disease progression, unacceptable toxicity, or death. The primary end point was confirmed intracranial objective response rate according to modified Response Evaluation Criteria in Solid Tumors version 1.1, which was primarily analyzed in the efficacy analysis set (EAS). A total of 45 patients were enrolled and treated (full analysis set), with 40 patients having at least one post-baseline tumor assessment (EAS). As of August 30, 2022, median follow-up duration was 12.5 months (95% confidence interval [CI]: 9.2-17.3). The confirmed intracranial objective response rate was 52.5% (95% CI: 36.1-68.5) in EAS and 46.7% (95% CI: 31.7-62.1) in full analysis set. The extracranial objective response rate was 47.5% (95% CI: 31.5-63.9) and 42.2% (95% CI: 27.7-57.8), respectively. Median intracranial progression-free survival was 7.6 months (95% CI: 4.6-not reached [NR]), median overall progression-free survival was 7.4 months (95% CI: 4.4-NR), and median overall survival was 21.0 months (95% CI: 15.9-NR). The most common treatment-related adverse events of grade 3 or higher were neutrophil count decrease (six [13.3%]) and anemia (four [8.9%]). One treatment-related death occurred owing to immune-related pneumonia. Linear mixed-effects model displayed that a positive trend for improvement in cognitive function and quality of life was observed based on Montreal Cognitive Assessment and Functional Assessment of Cancer Therapy-Lung scores (p = 0.025, p < 0.001). Camrelizumab plus pemetrexed and carboplatin was found to have an activity with manageable toxicity and to improve cognitive function and quality of life for patients with nonsquamous NSCLC with BMs in the first-line setting.
Nanvuranlat, an L-type amino acid transporter (LAT1) inhibitor for patients with pretreated advanced refractory biliary tract cancer (BTC): Primary endpoint results of a randomized, double-blind, placebo-controlled phase 2 study.
Authors: Junji Furuse, Masafumi Ikeda, Makoto Ueno, Masayuki Furukawa, Chigusa Morizane, Tetsuo Takehara, Tomohiro Nishina, Akiko Todaka, Naohiro Okano, Kazuo Hara, Yousuke Nakai, Kazuyoshi Ohkawa, Takashi Sasaki, Kazuya Sugimori, Naoyuki Yokoyama, Kouji Yamamoto
Journal: Journal of Clinical Oncology (2023)

494 Background: LAT1 is a transporter ( SLC7A5) of L-type amino acid. Overexpression in cancer cells supports aggressive proliferation. High expression of LAT1 in tumor specimens has been identified as a predictor of poor prognosis in patients with various cancer types, including BTC. The efficacy and safety of nanvuranlat (JPH203), a first-in-class, single agent that selectively inhibits LAT1, was evaluated in patients with pretreated, advanced, refractory BTC in a placebo-controlled randomized trial. Methods: Patients with four different subtypes of advanced BTC were enrolled: intrahepatic (IHC), extrahepatic (EHC), gallbladder (GBC) and ampulla of Vater (AVC). All were refractory to or intolerant of standard chemotherapy and other investigational medicines. Patients were pre-classified as non-rapid acetylators via N-acetyltransferase 2 ( NAT2), to maximize efficacy/safety by minimizing the metabolism of nanvuranlat. The primary endpoint was progression-free survival (PFS), assessed by blinded independent center review (BICR), using RECIST 1.1. Results: At data cut-off (February 28, 2022), 211 BTC patients were consented at 14 centers in Japan. Using NAT2 testing for classification, a total of 106 patients were randomized (2:1) to nanvuranlat (n = 70) or placebo (n = 36). Nanvuranlat met its primary endpoint and demonstrated a statistically significant improvement in PFS by BICR in comparison with the placebo group (Hazard Ratio = 0.557; 95% CI, 0.3435 – 0.9029; one-sided p = 0.0164). The disease control rate (DCR) in the nanvuranlat group was approximately 25% (average = 24.6%) across all BTC subtypes, while it was 11.4% in the placebo group. Grade 3 adverse events were reported in 30.0% for nanvuranlat vs 22.9% for placebo. Treatment-related adverse event rates were respectively 41.4% and 57.1% in the nanvuranlat and placebo groups. No patient had adverse events leading to nanvuranlat treatment discontinuation, dose reduction, or death. Conclusions: The study met the primary endpoint. LAT1 inhibitor monotherapy with nanvuranlat demonstrated useful clinical efficacy in patients with four different subtypes of pre-treated, advanced, refractory BTC. Safe and highly tolerated profile was also documented. Clinical trial information: UMIN000034080 .
A Tracheal Aspirate-derived Airway Basal Cell Model Reveals a Proinflammatory Epithelial Defect in Congenital Diaphragmatic Hernia
Authors: Richard Wagner, Gaurang M. Amonkar, Wei Wang, Jessica E. Shui, Kamakshi Bankoti, Wai Hei Tse, Frances A. High, Jill M. Zalieckas, Terry L. Buchmiller, Augusto Zani, Richard Keijzer, Patricia K. Donahoe, Paul H. Lerou, Xingbin Ai
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Congenital diaphragmatic hernia (CDH) is characterized by incomplete closure of the diaphragm and lung hypoplasia. The pathophysiology of lung defects in CDH is poorly understood. Objectives: To establish a translational model of human airway epithelium in CDH for pathogenic investigation and therapeutic testing. Methods: We developed a robust methodology of epithelial progenitor derivation from tracheal aspirates of newborns. Basal stem cells (BSCs) from patients with CDH and preterm and term non-CDH control subjects were derived and analyzed by bulk RNA sequencing, assay for transposase accessible chromatin with sequencing, and air–liquid interface differentiation. Lung sections from fetal human CDH samples and the nitrofen rat model of CDH were subjected to histological assessment of epithelial defects. Therapeutics to restore epithelial differentiation were evaluated in human epithelial cell culture and the nitrofen rat model of CDH. Measurements and Main Results: Transcriptomic and epigenetic profiling of CDH and control BSCs reveals a proinflammatory signature that is manifested by hyperactive nuclear factor kappa B and independent of severity and hernia size. In addition, CDH BSCs exhibit defective epithelial differentiation in vitro that recapitulates epithelial phenotypes found in fetal human CDH lung samples and fetal tracheas of the nitrofen rat model of CDH. Furthermore, blockade of nuclear factor kappa B hyperactivity normalizes epithelial differentiation phenotypes of human CDH BSCs in vitro and in nitrofen rat tracheas in vivo. Conclusions: Our findings have identified an underlying proinflammatory signature and BSC differentiation defects as a potential therapeutic target for airway epithelial defects in CDH.
<i>CCNE1</i>Amplification as a Therapeutic Target
Authors: George Au-Yeung, Linda Mileshkin, David D.L. Bowtell
Journal: Journal of Clinical Oncology (2023)

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Multicenter Phase II Trial of the WEE1 Inhibitor Adavosertib in Refractory Solid Tumors Harboring CCNE1 Amplification. December 05, 2022 ARTICLE CITATION DOI: 10.1200/JCO.22.02267 Journal of Clinical Oncology - published online before print February 2, 2023 PMID: 36730890 CCNE1 Amplification as a Therapeutic Target George Au-Yeung , MBBS, PhD1,2xGeorge Au-YeungSearch for articles by this author; Linda Mileshkin , MBBS, MD1,2xLinda MileshkinSearch for articles by this author; and David D.L. Bowtell , PhD1,2xDavid D.L. BowtellSearch for articles by this author Show More 1Peter MacCallum Cancer Center, Melbourne, Victoria, Australia2Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia https://doi.org/10.1200/JCO.22.02267 First Page Full Text PDF Figures and Tables © 2023 by American Society of Clinical OncologySUPPORTSupported by the National Health and Medical Research Council of Australia: APP1117044 (D.D.L.B.), APP1092856 (D.D.L.B.), and APP2008781 (D.D.L.B.).AUTHOR CONTRIBUTIONSConception and design: All authorsFinancial support: David D.L. BowtellCollection and assembly of data: George Au-Yeung, Linda MileshkinData analysis and interpretation: George Au-Yeung, Linda MileshkinManuscript writing: All authorsFinal approval of manuscript: All authorsAccountable for all aspects of the work: All authorsAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTCCNE1 Amplification as a Therapeutic TargetThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).George Au-YeungResearch Funding: Roche/Genentech (Inst), AstraZeneca (Inst)David D.L. BowtellConsulting or Advisory Role: Exo TherapeuticsResearch Funding: Roche/Genentech, AstraZeneca, BeiGenePatents, Royalties, Other Intellectual Property: Henry Jackson Foundation INOVA HealthCare University of Melbourne (Inst)No other potential conflicts of interest were reported. Companion Multicenter Phase II Trial of the WEE1 Inhibitor Adavosertib in Refractory Solid Tumors Harboring CCNE1 Amplification
CGM Metrics Identify Dysglycemic States in Participants From the TrialNet Pathway to Prevention Study
Authors: Darrell M. Wilson, Susan L. Pietropaolo, Maria Acevedo-Calado, Shuai Huang, Destiny Anyaiwe, David Scheinker, Andrea K. Steck, Madhuri M. Vasudevan, Siripoom V. McKay, Jennifer L. Sherr, Kevan C. Herold, Jessica L. Dunne, Carla J. Greenbaum, Sandra M. Lord, Michael J. Haller, Desmond A. Schatz, Mark A. Atkinson, Patrick W. Nelson, Massimo Pietropaolo
Journal: Diabetes Care (2023)

OBJECTIVE Continuous glucose monitoring (CGM) parameters may identify individuals at risk for progression to overt type 1 diabetes. We aimed to determine whether CGM metrics provide additional insights into progression to clinical stage 3 type 1 diabetes. RESEARCH DESIGN AND METHODS One hundred five relatives of individuals in type 1 diabetes probands (median age 16.8 years; 89% non-Hispanic White; 43.8% female) from the TrialNet Pathway to Prevention study underwent 7-day CGM assessments and oral glucose tolerance tests (OGTTs) at 6-month intervals. The baseline data are reported here. Three groups were evaluated: individuals with 1) stage 2 type 1 diabetes (n = 42) with two or more diabetes-related autoantibodies and abnormal OGTT; 2) stage 1 type 1 diabetes (n = 53) with two or more diabetes-related autoantibodies and normal OGTT; and 3) negative test for all diabetes-related autoantibodies and normal OGTT (n = 10). RESULTS Multiple CGM metrics were associated with progression to stage 3 type 1 diabetes. Specifically, spending ≥5% time with glucose levels ≥140 mg/dL (P = 0.01), ≥8% time with glucose levels ≥140 mg/dL (P = 0.02), ≥5% time with glucose levels ≥160 mg/dL (P = 0.0001), and ≥8% time with glucose levels ≥160 mg/dL (P = 0.02) were all associated with progression to stage 3 disease. Stage 2 participants and those who progressed to stage 3 also exhibited higher mean daytime glucose values; spent more time with glucose values over 120, 140, and 160 mg/dL; and had greater variability. CONCLUSIONS CGM could aid in the identification of individuals, including those with a normal OGTT, who are likely to rapidly progress to stage 3 type 1 diabetes.
Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets
Authors: Konrad Teodor Sawicki, Adam De Jesus, Hossein Ardehali
Journal: Circulation Research (2023)

The cardiovascular system requires iron to maintain its high energy demands and metabolic activity. Iron plays a critical role in oxygen transport and storage, mitochondrial function, and enzyme activity. However, excess iron is also cardiotoxic due to its ability to catalyze the formation of reactive oxygen species and promote oxidative damage. While mammalian cells have several redundant iron import mechanisms, they are equipped with a single iron-exporting protein, which makes the cardiovascular system particularly sensitive to iron overload. As a result, iron levels are tightly regulated at many levels to maintain homeostasis. Iron dysregulation ranges from iron deficiency to iron overload and is seen in many types of cardiovascular disease, including heart failure, myocardial infarction, anthracycline-induced cardiotoxicity, and Friedreich's ataxia. Recently, the use of intravenous iron therapy has been advocated in patients with heart failure and certain criteria for iron deficiency. Here, we provide an overview of systemic and cellular iron homeostasis in the context of cardiovascular physiology, iron deficiency, and iron overload in cardiovascular disease, current therapeutic strategies, and future perspectives.
Integrin-Dependent Cell–Matrix Adhesion in Endothelial Health and Disease
Authors: Jurjan Aman, Coert Margadant
Journal: Circulation Research (2023)

The endothelium is a dynamic, semipermeable layer lining all blood vessels, regulating blood vessel formation and barrier function. Proper composition and function of the endothelial barrier are required for fluid homeostasis, and clinical conditions characterized by barrier disruption are associated with severe morbidity and high mortality rates. Endothelial barrier properties are regulated by cell-cell junctions and intracellular signaling pathways governing the cytoskeleton, but recent insights indicate an increasingly important role for integrin-mediated cell-matrix adhesion and signaling in endothelial barrier regulation. Here, we discuss diseases characterized by endothelial barrier disruption, and provide an overview of the composition of endothelial cell-matrix adhesion complexes and associated signaling pathways, their crosstalk with cell-cell junctions, and with other receptors. We further present recent insights into the role of cell-matrix adhesions in the developing and mature/adult endothelium of various vascular beds, and discuss how the dynamic regulation and turnover of cell-matrix adhesions regulates endothelial barrier function in (patho)physiological conditions like angiogenesis, inflammation and in response to hemodynamic stress. Finally, as clinical conditions associated with vascular leak still lack direct treatment, we focus on how understanding of endothelial cell-matrix adhesion may provide novel targets for treatment, and discuss current translational challenges and future perspectives.
Aminophylline Treatment in Severe, Acute Asthma
Authors: Benjamin Littenberg
Journal: JAMA (1988)

Aminophylline is routinely recommended as a basic part of the emergency treatment of asthma. A comprehensive search found 13 reports of controlled trials of intravenous aminophylline therapy in severe, acute asthma. These studies compared aminophylline therapy with treatment with either albuterol (salbutamol), epinephrine, or other bronchodilators. The 13 reports did not agree. Seven reported no difference in spirometric values between aminophylline treatment and the control regimens. Three found aminophylline treatment superior. Three favored the control regimen. The results of the 13 trials were reanalyzed and pooled. Overall, there was no difference between the aminophylline-treated groups and the control groups. Sensitivity analysis suggests that aminophylline therapy is ineffective alone but may be more effective than single-drug therapy when combined with an injected β-agonist. Despite widespread practice, available trials do not provide adequate evidence to support or reject the use of aminophylline in the treatment of severe, acute asthma. (<i>JAMA</i>1988;259:1678-1684)
Treatment Decisions in the Mentally Impaired
Authors: Erich H. Loewy
Journal: New England Journal of Medicine (1987)

In working with mentally impaired patients of any age, we frequently encounter the problem of what treatment is and is not justified. Often physicians may think that although all-out measures to preserve life — such as complicated surgery — are not justified, more simple means to treat intercurrent illness are clearly warranted. At other times, physicians feel compelled to treat even when the therapy is clearly ill advised. When patients' wishes are unknown or unknowable, physicians may treat even against their better judgment,1 not only because to do otherwise would run contrary to their innermost instincts but also because there . . .
Withholding of Life-Sustaining Treatment From the Terminally III, Incompetent Patient: Who Decides?
Authors: Daniel G. Suber
Journal: JAMA (1982)

Part I of this article traced the early development of the law regarding decisions to discontinue potentially life-prolonging treatment of terminally ill patients (1982; 248:2250). In the seminal case of<i>In re Quinlan</i>, 355 A2d 647 (NJ 1976), the New Jersey Supreme Court held that a patient's constitutional right of privacy includes the right to refuse treatment where such treatment can only perpetuate a comatose, vegetative existence. Furthermore, this privacy right may be exercised on the incompetent patient's behalf by the guardian, family, and attending physicians, with the approval of the ethics committee of the hospital involved. Subsequent decisions in other jurisdictions have endorsed<i>Quinlan's</i>constitutional rights analysis and have adopted, in principle, the concept of "substituted judgment." Many courts have rejected<i>Quinlan's</i>formula for private decision making, however, opting instead to delineate guidelines for determining when judicial approval is required to implement nontreatment decisions.<i>Superintendent of Belchertown State School</i>
Emergency Treatment of Asthma
Authors: Gordon W. Josephson
Journal: JAMA (1979)

The effectiveness of epinephrine was compared to that of a combination of epinephrine and aminophylline in the initial treatment of acute asthma. Forty-four patients with 51 episodes of acute asthma were evaluated. Peak flow spirometry served as an objective measure of airway resistance, and theophylline levels were determined at fixed intervals throughout the study. Epinephrine and aminophylline were not found to be superior to epinephrine alone. There was no correlation between mean serum theophylline levels and the magnitude of improvement. Rapidity of emergency department discharge and frequency of admission was independent of treatment method. The failure of epinephrine-aminophylline to effect more rapid or profound improvement in pulmonary function might suggest that epinephrine alone, or an equivalent sympathomimetic is a rational choice in the initial treatment of acute asthma. (<i>JAMA</i>242:639-643, 1979)
Bronchiolitis and Bronchitis in Connective Tissue Disease
Authors: Gary R. Epler
Journal: JAMA (1979)

Rapid onset of severe and irreversible airflow obstruction developed in two women. One had eosinophilic fasciitis and the other had rheumatoid arthritis. Both were treated with penicillamine. In the first patient, aged 42 years, dyspnea developed after six months of therapy. Her roentgenogram showed hyperinflation. Forced vital capacity expired in one second (FEV<sub>1</sub>/FVC%) decreased from 75% to 40%, and the residual volume increased by 1 L. In the second patient, aged 54 years, cough and dyspnea developed after ten months of therapy. The FEV<sub>1</sub>/FVC% was 56%, the FEV<sub>1</sub>was 0.9 L, and the roentgenogram was normal. Lung biopsy specimens demonstrated severe and widespread bronchiolitis. An association between obliterative bronchiolitis and rheumatoid arthritis has been reported. Penicillamine may impair healing of bronchiolitis in such patients. (<i>JAMA</i>242:528-532, 1979)
Pleural Effusion
Authors: Donald D. Storey
Journal: JAMA (1976)

The cause of pleural effusion in 108 of 133 patients was determined by laboratory tests and clinical examination; it was indeterminate in 25, even after complete diagnostic evaluation. In 164 diagnostic thoracenteses, 136 cytologic examinations were done; the results were positive for cancer in 20 (15%). Five of 19 patients (26%) with bronchogenic cancer, 13 of 25 (52%) with metastatic cancer of the lung, and two of 20 (10%) with lymphoma had positive results on cytologic examination. Of 143 routine bacterial cultures, only five were positive (3%). Of 103 mycobacterial and 76 fungal cultures, only one was positive in each instance. Despite the high incidence of indeterminate diagnoses, we recommend that only measurement of protein content and cytologic examination be ordered routinely. Our algorithm provides a logical, cost-effective approach to the diagnostic problem of pleural effusion. (<i>JAMA</i>236:2183-2186, 1976)
Dealing With the Long-Term Social Implications of Research
Authors: Alan Fleischman, Carol Levine, Lisa Eckenwiler, Christine Grady, Dale E. Hammerschmidt, Jeremy Sugarman
Journal: The American Journal of Bioethics (2011)

Biomedical and behavioral research may affect strongly held social values and thereby create significant controversy over whether such research should be permitted in the first place. Institutional review boards (IRBs) responsible for protecting the rights and welfare of participants in research are sometimes faced with review of protocols that have significant implications for social policy and the potential for negative social consequences. Although IRB members often raise concerns about potential long-term social implications in protocol review, federal regulations strongly discourage IRBs from considering them in their decisions. Yet IRBs often do consider the social implications of research protocols and sometimes create significant delays in initiating or even prevent such research. The social implications of research are important topics for public scrutiny and professional discussion. This article examines the reasons that the federal regulations preclude IRBs from assessing the social risks of research, and examines alternative approaches that have been used with varying success by national advisory groups to provide such guidance. The article concludes with recommendations for characteristics of a national advisory group that could successfully fulfill this need, including sustainability, independence, diverse and relevant expertise, and public transparency.
Psychological Factors in Rheumatism, Part I
Authors: J. L. Halliday
Journal: BMJ (1937)

MEDICALJOURAL 213 done to determine exactly what value radon has in the treatment of gout.The erythrocyte count, however, showed a tendency to fall when large doses were employed, in certain instances to a serious degree.It appears, therefore, that with large dosage the administration of radon is attended by definite risk, and it should be administered with great caution.